Molecular design of peptide therapeutics via N-terminal modification
Glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon are three naturally occurring peptide hormones that mediate glucoregulation. Several agonists representing appropriately modified native ligands have been developed to maximize metabolic benefits with reduced side-ef...
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| Veröffentlicht in: | Methods in enzymology 2024, Vol.698, p.195 |
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| creator | Sürmeli, Damla Dinsmore, Tristan C Anchukaitis, Haley M Montanari, Vittorio Beinborn, Martin Kumar, Krishna |
| description | Glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon are three naturally occurring peptide hormones that mediate glucoregulation. Several agonists representing appropriately modified native ligands have been developed to maximize metabolic benefits with reduced side-effects and many have entered the clinic as type 2 diabetes and obesity therapeutics. In this work, we describe strategies for improving the stability of the peptide ligands by making them refractory to dipeptidyl peptidase-4 catalyzed hydrolysis and inactivation. We describe a series of alkylations with variations in size, shape, charge, polarity, and stereochemistry that are able to engender full activity at the receptor(s) while simultaneously resisting enzyme-mediated degradation. Utilizing this strategy, we offer a novel method of modulating receptor activity and fine-tuning pharmacology without a change in peptide sequence. |
| doi_str_mv | 10.1016/bs.mie.2024.04.011 |
| format | Article |
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Several agonists representing appropriately modified native ligands have been developed to maximize metabolic benefits with reduced side-effects and many have entered the clinic as type 2 diabetes and obesity therapeutics. In this work, we describe strategies for improving the stability of the peptide ligands by making them refractory to dipeptidyl peptidase-4 catalyzed hydrolysis and inactivation. We describe a series of alkylations with variations in size, shape, charge, polarity, and stereochemistry that are able to engender full activity at the receptor(s) while simultaneously resisting enzyme-mediated degradation. Utilizing this strategy, we offer a novel method of modulating receptor activity and fine-tuning pharmacology without a change in peptide sequence.</description><identifier>ISSN: 1557-7988</identifier><identifier>EISSN: 1557-7988</identifier><identifier>DOI: 10.1016/bs.mie.2024.04.011</identifier><identifier>PMID: 38886032</identifier><language>eng</language><publisher>United States</publisher><subject>Alkylation ; Animals ; Diabetes Mellitus, Type 2 - drug therapy ; Diabetes Mellitus, Type 2 - metabolism ; Dipeptidyl Peptidase 4 - chemistry ; Dipeptidyl Peptidase 4 - metabolism ; Drug Design ; Gastric Inhibitory Polypeptide - chemistry ; Gastric Inhibitory Polypeptide - metabolism ; Glucagon - chemistry ; Glucagon - metabolism ; Glucagon-Like Peptide 1 - chemistry ; Glucagon-Like Peptide 1 - metabolism ; Glucagon-Like Peptide-1 Receptor - metabolism ; Humans ; Hydrolysis ; Ligands ; Peptides - chemistry</subject><ispartof>Methods in enzymology, 2024, Vol.698, p.195</ispartof><rights>Copyright © 2024. 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Utilizing this strategy, we offer a novel method of modulating receptor activity and fine-tuning pharmacology without a change in peptide sequence.</description><subject>Alkylation</subject><subject>Animals</subject><subject>Diabetes Mellitus, Type 2 - drug therapy</subject><subject>Diabetes Mellitus, Type 2 - metabolism</subject><subject>Dipeptidyl Peptidase 4 - chemistry</subject><subject>Dipeptidyl Peptidase 4 - metabolism</subject><subject>Drug Design</subject><subject>Gastric Inhibitory Polypeptide - chemistry</subject><subject>Gastric Inhibitory Polypeptide - metabolism</subject><subject>Glucagon - chemistry</subject><subject>Glucagon - metabolism</subject><subject>Glucagon-Like Peptide 1 - chemistry</subject><subject>Glucagon-Like Peptide 1 - metabolism</subject><subject>Glucagon-Like Peptide-1 Receptor - metabolism</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Ligands</subject><subject>Peptides - chemistry</subject><issn>1557-7988</issn><issn>1557-7988</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNj0lLBDEYRIMozjj6BzxIjl66zdLZjjKOC4x60XOTTr5opDc7acF_74AjCAWvDo-CQuickpISKq-aVHYRSkZYVZJdKD1ASyqEKpTR-vBfX6CTlD4IYUobeowWXGstCWdLdPM4tODm1k7YQ4pvPR4CHmHM0QPO7zDZEeYcXcJf0eKnIsPUxd62uBt8DNHZHIf-FB0F2yY423OFXm83L-v7Yvt897C-3hYjZTIXhjchGOOpsdQJxgNIEJUPsoFKOwJM-CAE0VJaw7wT2kpmCCjuGitVqPgKXf7ujtPwOUPKdReTg7a1PQxzqjlRRBlOpN6pF3t1bjrw9TjFzk7f9d9z_gMPblxy</recordid><startdate>2024</startdate><enddate>2024</enddate><creator>Sürmeli, Damla</creator><creator>Dinsmore, Tristan C</creator><creator>Anchukaitis, Haley M</creator><creator>Montanari, Vittorio</creator><creator>Beinborn, Martin</creator><creator>Kumar, Krishna</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>2024</creationdate><title>Molecular design of peptide therapeutics via N-terminal modification</title><author>Sürmeli, Damla ; Dinsmore, Tristan C ; Anchukaitis, Haley M ; Montanari, Vittorio ; Beinborn, Martin ; Kumar, Krishna</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p126t-93bff99d19a1c523fe6e54df6be48c0e25df550866a92dc58a6290e73cba67f43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Alkylation</topic><topic>Animals</topic><topic>Diabetes Mellitus, Type 2 - drug therapy</topic><topic>Diabetes Mellitus, Type 2 - metabolism</topic><topic>Dipeptidyl Peptidase 4 - chemistry</topic><topic>Dipeptidyl Peptidase 4 - metabolism</topic><topic>Drug Design</topic><topic>Gastric Inhibitory Polypeptide - chemistry</topic><topic>Gastric Inhibitory Polypeptide - metabolism</topic><topic>Glucagon - chemistry</topic><topic>Glucagon - metabolism</topic><topic>Glucagon-Like Peptide 1 - chemistry</topic><topic>Glucagon-Like Peptide 1 - metabolism</topic><topic>Glucagon-Like Peptide-1 Receptor - metabolism</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>Ligands</topic><topic>Peptides - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sürmeli, Damla</creatorcontrib><creatorcontrib>Dinsmore, Tristan C</creatorcontrib><creatorcontrib>Anchukaitis, Haley M</creatorcontrib><creatorcontrib>Montanari, Vittorio</creatorcontrib><creatorcontrib>Beinborn, Martin</creatorcontrib><creatorcontrib>Kumar, Krishna</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>Methods in enzymology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sürmeli, Damla</au><au>Dinsmore, Tristan C</au><au>Anchukaitis, Haley M</au><au>Montanari, Vittorio</au><au>Beinborn, Martin</au><au>Kumar, Krishna</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Molecular design of peptide therapeutics via N-terminal modification</atitle><jtitle>Methods in enzymology</jtitle><addtitle>Methods Enzymol</addtitle><date>2024</date><risdate>2024</risdate><volume>698</volume><spage>195</spage><pages>195-</pages><issn>1557-7988</issn><eissn>1557-7988</eissn><abstract>Glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon are three naturally occurring peptide hormones that mediate glucoregulation. 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| ispartof | Methods in enzymology, 2024, Vol.698, p.195 |
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| subjects | Alkylation Animals Diabetes Mellitus, Type 2 - drug therapy Diabetes Mellitus, Type 2 - metabolism Dipeptidyl Peptidase 4 - chemistry Dipeptidyl Peptidase 4 - metabolism Drug Design Gastric Inhibitory Polypeptide - chemistry Gastric Inhibitory Polypeptide - metabolism Glucagon - chemistry Glucagon - metabolism Glucagon-Like Peptide 1 - chemistry Glucagon-Like Peptide 1 - metabolism Glucagon-Like Peptide-1 Receptor - metabolism Humans Hydrolysis Ligands Peptides - chemistry |
| title | Molecular design of peptide therapeutics via N-terminal modification |
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